Cobalt dodecenedioate for treating canine pyometritis

ABSTRACT

THE COBALT SALT OF TRANS-DODECENEDIOIC ACID HAS BEEN PREPARED AND FOUND TO BE A HIGHLY EFFECTIVE AGENT AGAINST CANINE PYOMETRITIS.

United States Patent Office 3,808,314 Patented Apr. 30, 1974 Int. Cl.A61k 27/00 US. Cl. 424-295 1 Claim ABSTRACT OF THE DISCLOSURE The cobaltsalt of trans-dode'cenedioic acid has been prepared and found to be ahighly effective agent against canine pyometritis.

This application is a division of and incorporates by reference myearlier copending application, Ser. No. 10,680, now United States Pat.No. 3,720,773, issued Mar. 13, 1973, which application Ser. No. 10,680is a division of and incorporates by reference earlier filed UnitedStates application No. 715,167, now US. Pat. No. 3,542,826 issued Nov.24, 1970.

BACKGROUND OF THE INVENTION Field of the invention The invention isconcerned with the cobalt salt of trans-dodecenedioic acid (TTA) and itsuse in the treatment of canine pyometritis.

Prior art Aloe Vera in its unextracted form has been used for centuriesfor its vulnerary therapeutic effectiveness, particularly against burns.TTA is obtainable by exhaustive extraction of Aloe Vera or may besynthetically produced. The cobalt salt of TTA is a new compound.

SUMMARY OF THE INVENTION It has now been discovered that the cobalt saltof TTA is vastly more effective than TTA or Aloe Vera in treatment ofcanine pyometritis.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Traumatic acid is also known as1-decene-l,l0-dicarboxylic acid and exists in cis and trans forms, thelatter, hereinafter referred to as TTA, being the more biologicallyactive.

TTA may be prepared as follows: Undecylenic acid is oxidized tohydroxyformoxyhendecanoic acid with hydrogen peroxide in formic acidwhich is then hydrolyzed to 10,11 dihydroxyhendecanoic acid with sodiumhydroxide. Treatment with periodic acid transforms the 10,ll-dihydroxyhendecanoic acid into the sebacic semi-aldehyde which iscondensed with malonic acid in the presence of pyridine. 'Uponacidification of the condensation mixture, l-decane-l,IO-dicarboxylicacid, i.e. traumatic acid, precipitates. This product is purified byrecrystallization from a solvent. While the acid per se is biologicallyactive, the cobalt salt is many times more active.

Salts of TTA are prepared by replacement of the carbonyl hydrogen withcobalt from a suitable metal salt, e.g. carbonate, acetate, chloride andthe like, e.g. cobalt carbonate.

Quantities of traumatic acid or salt employed are typically quite small.Thus as little as 0.00005 percent are suitable.

The cobaltous TTA is applied topically in a suitable carrier e.g.liquids such as water, physiological saline, aqueous alcohol, or inointments, salves, creams, lotions which are pharmaceutically acceptableand either inert or possessed of beneficial properties themselves.

Preparation of TTA A one liter three-necked flask is equipped with amechanical stirrer, a thermometer and a dropping funnel. In the flaskare placed 184 g. (1 mole) of undecylenic acid and 200 g. (4.15 moles)of formic acid. The stirrer is started and the reaction mixture iswarmed by a water bath to 40 C. for at least one-half hour longer afterall the peroxide has been added.

The reaction mixture is transferred to a suitable flask for vacuumdistillation and the formic acid and any water is removed by distillingunder full vacuum of the water pump. The residualhydroxyformoxyhendecanoic acid is now ready for hydrolysis. This isaccomplished by boiling for one hour and acidified to a pH of 2, orslightly lower with 6 N hydrochloric acid. After cooling well in an icebath, the solid acid is collected on a Buchner funnel (pre-chilled),washed with ice water and sucked as dry as possible. The solid is driedin a vacuum desiccator over flake sodium hydroxide, 205.0 g. of productequal to 93.92% of the theoretical yield were obtained.

A solution of 42.78 g. (0.2 mole) of sodium metaperiodate (NalO in 600ml. of 1 N sulfuric acid is prepared. In a 1 liter flask equipped with amechanical stirrer, a thermometer and a dropping funnel are placed 400ml. of ethanol and 43.6 g. (0.2 mole) of 10,11-dihydroxyhendecanoicacid. This solution is warmed to 40 C. and the periodate solution isadded through the separatory funnel at a rapid rate while stirring themixture. The temperature is maintained at 40 C. for 3040 minutes afterwhich the solution is cooled to 20 C., and any inorganic salts thatseparated were collected on a 'Buchner funnel, sucked dry and washedwith ether to remove adherent organic material.

The ether washing is used to extract the aqueous filtrate along withadditional ether as may be needed. A total of three extractions withabout 200 ml. of ether in each extraction should be used. The combinedether extract is shaken with a small amount of anhydrous sodium sulfateto remove most of the water, after which the ether is distilled. Theresidual oil is then submitted to the full vacuum of a water pump toremove any alcohol and water remaining. An oily residue sebacicsemi-aldehyde, weighing 3.0 g. is obtained. (96.77% of theoreticalyield.) This product is used in the next step without furtherpurification.

18.6 g. (0.1 mole) of the sebacic semi-aldehyde is mixed with 11.45 g.(0.11 mole) of malonic acid and 10.28 g. (0.13 mole) of pyridine in a500 ml. round bottom flask. The mixture is allowed to stand for 24 hoursat room temperature and then heated for 5 hours on a steam bath. Themixture is then cooled and diluted with about 10 volumes of water. Uponacidification to pH 2 with 2 N sulfuric acid and chilled to near 0 C.,the crude l-decane-l,IO-dicarboxylic acid is collected on a Buchnerfunnel. It is sucked dry and washed with a' small amount of ice coldwater. Dry in a vacuum desiccator over flake caustic. The crudetrans-l-decene-l,IO-dicarboxylic acid, weighing 18.0 g., isrecrystallized twice from boiling solvent. The yield is 11.49 g. (50.33%of theory).

The dicar-boxylic acid obtained in this fashion has a molecular formula0 13 0 molecular weight 228.28, melts at 161 -165 0., when crystallizedfrom ethyl acetate, contains an unsaturated linkage, is very sparinglysoluble in water but fairly soluble in alcohol, ethyl acetate, benzol,chloroform, ether, glycerin, propylene glycol, is acid and shows aneutralization equivalent of 115, indicating dibasicity.

Similar acids to TTA have been identified by plant physiologists asamong the many factors involved in plant growth phenomena, and numerousclosely allied acids have been synthesized e.g. having formulas of thetype HOOC(CH ),,CH=CHCOOH and The following dicarboxylic acids failed toeffect any acceleration of wound healing in experimentally inducedwounds in rabbit ears over controls in opposite ears as opposed to thetransdodecanedioic acid, which speeds up repair appreciably:1-nonene-l,9-, 2-nonene-1,9-, 2-decene-1,10-, l-tridecene-1,13-, and2-tridecene-l,13 dicarboxylic acid.

The cobalt salt of TTA is far more effective than TTA.

It is noteworthy that transdodecenedioic acid is the therapeuticallyeffective in the treatment of diseases of animals namely caninepyometritis.

Preparation of TTA cobalt salt Three hundred milligrams of TTA weredissolved in 300 millimeters of boiling distilled water. An excess ofcohalt carbonate, 250 milligrams, was added to the boiling solution,forming a pink-violet slurry. After minutes of continued boiling, andfiltering, the filtrate was evaporated to about 150 millimeters and letstand overnight. Two sets of crystals formed the first, on the bottom ofthe container, were long (1.3 millimeters) and ruby-red. The second setwere colorless and floated on the filtrate liquid. The rubyred crystalswere separated by decanting the other crystals and filtrate and dried onunglazed porcelain. After recrystallization from distilled water, ayield of milligrams of ruby-red powder was realized. Quantitativeanalysis revealed a"c'obalt content in the powder of 20l58%.

In close agreement with a single cobalt salt of TI A (the0r.: 20.593%

'Cobalt dodecendioate is therapeutically effective in microgram dose,whether applied topically in any convenient compatible formulationpreferably free of inhibiting antimetabolites, or injected in solutionform, or administered perorally, or included in rectal or vaginalsuppository form, or as a microor other clyama.

A completely unpredicted effect of the salt is its action towardinfections in animals.

Aside from its use alone, either the cobalt TTA may be used in admixturewith other medication and presented in the form of soaps, ointments,lotions and such other forms as are common to the dispensation of drugand medicated cosmetic formulations.

I claim:

1. Method of treating canine pyometritis which comprises applyingtopically to the canine in need of said treatment cobaltoustranstraumatate in an effective amount for treating canine pyometritis.

OTHER REFERENCES Noller: Chemistry of Organic Compounds, W. B. SaundersCo., Philadelphia, 1965, p. 181.

JEROME D. GOLDBERG, Primary Examiner

